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Safety and Efficacy of BIBF 1120 at High Dose in Idiopathic Pulmonary Fibrosis Patients II

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01335477
Recruitment Status : Completed
First Posted : April 14, 2011
Results First Posted : February 13, 2015
Last Update Posted : July 25, 2016
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Pulmonary Fibrosis
Interventions Drug: placebo
Drug: BIBF 1120
Enrollment 551
Recruitment Details  
Pre-assignment Details  
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Period Title: Overall Study
Started 220 331
Completed 179 272
Not Completed 41 59
Reason Not Completed
Adverse Event             30             42
Non compliant with protocol             0             2
Lost to Follow-up             1             2
Consent withdrawn, not due to AE             7             9
Not treated             1             2
Reason other than those stated above             2             2
Arm/Group Title Placebo Nintedanib 150 mg Bid Total
Hide Arm/Group Description Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Total of all reporting groups
Overall Number of Baseline Participants 219 329 548
Hide Baseline Analysis Population Description
Treated Set (TS): The TS consisted of randomized patients who were dispensed study medication and were documented to have taken at least one dose of investigational treatment.
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 219 participants 329 participants 548 participants
67.1  (7.5) 66.4  (7.9) 66.6  (7.8)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 219 participants 329 participants 548 participants
Female
48
  21.9%
73
  22.2%
121
  22.1%
Male
171
  78.1%
256
  77.8%
427
  77.9%
1.Primary Outcome
Title Annual Rate of Decline in Forced Vital Capacity (FVC) Over 52 Weeks.
Hide Description

Forced vital capacity (FVC) is the total amount of air exhaled during the lung function test.

For this endpoint reported means represent the adjusted rate.

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Mean (Standard Error)
Unit of Measure: mL/year
-207.32  (19.309) -113.59  (15.726)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments

Random coefficient regression with fixed effects for treatment, gender, age, height and random effect of patient specific intercept and time.

A hierarchical procedure was used in order to demonstrate the superiority of nintedanib over placebo for one primary and two key secondary endpoints.

The consecutive steps of the hierarchy were only considered if the previous step was significant at the one-sided 2.5% level and the results were in favour of nintedanib.

Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0002
Comments The objective of this trial was to assess the superiority of nintedanib 150 mg bid compared to placebo on the annual rate of decline in FVC.
Method Random coefficient regression
Comments The Roger-Kenward approximation was used to estimate denominators degrees of freedom.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 93.73
Confidence Interval 95%
44.78 to 142.68
Parameter Dispersion
Type: Standard Error of the mean
Value: 24.907
Estimation Comments

Within-patient errors are modelled by an Unstructured variance-covariance matrix.

Inter-individual variability is modelled by a Variance-components variance-covariance matrix.

Nintedanib 150 mg bid versus Placebo.

2.Secondary Outcome
Title Change From Baseline in Saint George's Respiratory Questionnaire (SGRQ) Total Score at 52 Weeks
Hide Description

This is a key secondary endpoint. SGRQ is a health-related quality of life questionnaire divided into 3 components : symptoms, activity and impact.

The total score (summed weights) can range from 0 to 100 with a lower score denoting a better health status.

Means provided are the adjusted means based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 213 320
Mean (Standard Error)
Unit of Measure: points on a scale
5.48  (0.891) 2.80  (0.730)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Total score, baseline SGRQ Total score-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0197
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.69
Confidence Interval 95%
-4.95 to -0.43
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.151
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

3.Secondary Outcome
Title Time to First Acute Idiopathic Pulmonary Fibrosis (IPF) Exacerbation
Hide Description

Due to rare events, the median of time to event is not calculable, thus the percentages of patients with (IPF) exacerbation are reported and represented as a key secondary endpoint. An acute exacerbation (reported as an AE by the investigator) was defined as follows:

Otherwise unexplained clinical features including all of the following:

Unexplained worsening or development of dyspnoea within 30 days New diffuse pulmonary infiltrates on chest X-ray, and/or new HRCT parenchymal abnormalities with no pneumothorax or pleural effusion (new ground-glass opacities) since the last visit Exclusion of infection as per routine clinical practice and microbiological studies Exclusion of alternative causes as per routine clinical practice including left heart failure, pulmonary embolism and identifiable cause of acute lung injury.

Failure is the proportion of patients with at least one acute IPF exacerbation over 52 weeks, based on all investigator-reported AEs .

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 9.6 3.6
Censored 90.4 96.4
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard Ratio is based on a Cox's regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0050
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.38
Confidence Interval 95%
0.19 to 0.77
Estimation Comments Nintedanib 150 mg bid versus Placebo.
4.Secondary Outcome
Title Absolute Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks
Hide Description Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 217 327
Mean (Standard Error)
Unit of Measure: mL
-205.03  (16.629) -95.26  (14.200)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 109.77
Confidence Interval 95%
70.92 to 148.62
Parameter Dispersion
Type: Standard Error of the mean
Value: 19.808
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

5.Secondary Outcome
Title Relative Change From Baseline in Forced Vital Capacity (FVC) Over 52 Weeks
Hide Description Percentage change from baseline in FVC over 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 217 327
Mean (Standard Error)
Unit of Measure: percent change
-8.14  (0.620) -3.90  (0.528)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC, baseline FVC-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.24
Confidence Interval 95%
2.78 to 5.69
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.742
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

6.Secondary Outcome
Title Absolute Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks
Hide Description Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 217 327
Mean (Standard Error)
Unit of Measure: %predicted
-6.15  (0.505) -3.09  (0.433)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted], baseline FVC [%predicted]-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 3.06
Confidence Interval 95%
1.87 to 4.25
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.607
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

7.Secondary Outcome
Title Relative Change From Baseline in Forced Vital Capacity (FVC) (% Predicted) Over 52 Weeks
Hide Description Percentage change from baseline in FVC (% predicted) at 52 weeks. Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 217 327
Mean (Standard Error)
Unit of Measure: percent change
-8.13  (0.614) -3.92  (0.525)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Based on Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline FVC [%predicted], baseline FVC [%predicted]-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 4.21
Confidence Interval 95%
2.76 to 5.67
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.743
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

8.Secondary Outcome
Title Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 5% Threshold
Hide Description Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 5% threshold (decrease by >5%, increase by >5%, and change within ≤5%).
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (for patients with change from baseline in FVC (% predicted) at Week 52)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 180 269
Measure Type: Number
Unit of Measure: percentage of participants
Decrease > 5% 52.2 34.9
Change within ≤ 5% 45.0 50.2
Increase > 5% 2.8 14.9
9.Secondary Outcome
Title Absolute Categorical Change From Baseline of FVC (% Predicted) by Categories Over 52 Weeks - 10% Threshold
Hide Description Absolute categorical change of FVC (% predicted) by categories over 52 weeks - 10% threshold (decrease by 10%, increase by >10%, and change within ≤10%)
Time Frame Baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (for patients with change from baseline in FVC (% predicted) at Week 52)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 180 269
Measure Type: Number
Unit of Measure: percentage of participants
Decrease > 10% 22.2 14.9
Change within ≤ 10% 77.2 80.7
Increase > 10% 0.6 4.5
10.Secondary Outcome
Title FVC Responders Using 10% Threshold at 52 Weeks
Hide Description FVC responders using 10% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 10% and with an FVC evaluation at 52 weeks.
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
63.93
(57.38 to 70.00)
69.60
(64.43 to 74.33)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Logistic regression with terms treatment, age, gender, height and baseline FVC % predicted
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1833
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.286
Confidence Interval 95%
0.89 to 1.86
Estimation Comments Nintedanib 150 mg bid versus Placebo
11.Secondary Outcome
Title Proportion of FVC Responders Using 5% Threshold at 52 Weeks
Hide Description Proportion of FVC responders using 5% threshold at 52 weeks, defined as patients with absolute decline in FVC% predicted no greater than 5% and with an FVC evaluation at 52 weeks.
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
39.27
(33.04 to 45.87)
53.19
(47.79 to 58.52)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Logistic regression with terms treatment, age, gender, height and baseline FVC % predicted.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0011
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.794
Confidence Interval 95%
1.26 to 2.55
Estimation Comments Nintedanib 150 mg bid versus Placebo
12.Secondary Outcome
Title Proportion of SGRQ Responders at 52 Weeks: Patient Reported Outcomes (PROs)
Hide Description

Proportion of SGRQ responders at 52 weeks.

Responders defined as <= -4 points change in change from baseline in SGRQ total score at 52 weeks.

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
16.89
(12.51 to 22.42)
25.23
(20.84 to 30.19)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Logistic regression with terms treatment, baseline SGRQ total score
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0218
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.664
Confidence Interval 95%
1.08 to 2.57
Estimation Comments Nintedanib 150 mg bid versus Placebo
13.Secondary Outcome
Title Change From Baseline in SGRQ Symptom Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
Hide Description

SGRQ Symptom score is a sub-component of SGRQ total score and is concerned with the effect of respiratory symptoms, their frequency and severity. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better symptom-related quality of life.

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 214 323
Mean (Standard Error)
Unit of Measure: points on a scale
3.43  (1.297) 2.03  (1.061)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Symptoms component, baseline SGRQ Symptoms component-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.4019
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -1.40
Confidence Interval 95%
-4.69 to 1.88
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.675
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

14.Secondary Outcome
Title Change From Baseline in SGRQ Impact Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
Hide Description

SGRQ Impact score is a sub-component of SGRQ total score and covers a range of aspects concerned with social functioning and psychological disturbances resulting from airway disease. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better impact-related quality of life.

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 215 320
Mean (Standard Error)
Unit of Measure: points on a scale
5.93  (1.036) 2.85  (0.852)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ impact component, baseline SGRQ impact component-by-visit and random effect for patient
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0220
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.08
Confidence Interval 95%
-5.71 to -0.45
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.342
Estimation Comments

Within-patient error are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

15.Secondary Outcome
Title Change From Baseline in SGRQ Activity Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
Hide Description

SGRQ Activity score is a sub-component of SGRQ total score and concerned with activities that cause or are limited by breathlessness. This score calculated as summed weights ranges from 0 to 100 with lower score denoting a better activity-related quality of life.

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 214 322
Mean (Standard Error)
Unit of Measure: points on a scale
7.20  (1.052) 3.89  (0.863)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ Activities component, baseline SGRQ Activities component-by-visit and random effect for patient
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0152
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.31
Confidence Interval 95%
-5.97 to -0.64
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.360
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

16.Secondary Outcome
Title Change From Baseline in Idiopathic Pulmonary Fibrosis (IPF) Specific Version of SGRQ (SGRQ-I) Total Score at 52 Weeks (Points): Patient Reported Outcomes (PROs)
Hide Description

SGRQ-I is the IPF specific version of SGRQ comprises of selected items from the SGRQ divided into three components, Symptoms, Activity and Impact. Each component is scored separately. The weights for all items with a positive responses are summed and the weights from missed items are deducted from the maximum possible weight for the total score.

The total score is calculated by dividing the summed weights from positive items in the questionnaire by maximum possible weight for all items in the questionnaire. The total score can range from 0 to 100 with a lower score denoting a better health-related quality of life. Change from baseline is calculated as the difference between total score at week 52 and total score at baseline as measured by the scale.

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 213 320
Mean (Standard Error)
Unit of Measure: points on a scale
5.84  (0.921) 2.72  (0.757)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SGRQ-I Total score, baseline SGRQ-I Total score-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0089
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -3.12
Confidence Interval 95%
-5.46 to -0.79
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.192
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

17.Secondary Outcome
Title Change From Baseline in Shortness of Breath Questionnaire (SOBQ) at 52 Weeks: Patient Reported Outcomes (PROs)
Hide Description

Shortness of Breath Questionnaire measures the shortness of breath. It comprises of 24 items. Each item is scored on a scale between 0-5 where 5 represents maximal breathlessness. The responses to all items are summed up to provide the overall score that can range from 0 (best outcome) to 120 (worst outcome).

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 204 302
Mean (Standard Error)
Unit of Measure: points on a scale
9.07  (1.300) 6.69  (1.073)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline SOBQ score, baseline SOBQ score-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1587
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -2.38
Confidence Interval 95%
-5.68 to 0.93
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.685
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

18.Secondary Outcome
Title Change From Baseline in Cough Symptom Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)
Hide Description

The cough domains of the Cough and Sputum Assessment Questionnaire (CASAQ(CD)) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome).

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 215 323
Mean (Standard Error)
Unit of Measure: points on a scale
-2.38  (1.325) -0.33  (1.087)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline CASA-Q Cough symptoms score, baseline CASA-Q Cough symptoms score-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2326
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 2.05
Confidence Interval 95%
-1.31 to 5.41
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.713
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

19.Secondary Outcome
Title Change From Baseline in Cough Impact Score of the Cough and Sputum Assessment Questionnaire (CASA-Q) Score at 52 Weeks: Patient Reported Outcomes (PROs)
Hide Description

The cough domains of the Cough and Sputum Assessment Questionnaire (CASA- Q) assess the frequency and severity of cough and sputum and their impact on everyday life. It contains 4 domains cough/sputum symptom and impact with each scale ranging from 0 to 100 with lower scores indicating higher symptoms/impact levels (worst outcome).

Means presented are the adjusted means and are based on all analyzed patients in the model (not only patients with a baseline and measurement at week 52).

Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 215 322
Mean (Standard Error)
Unit of Measure: points on a scale
-4.39  (1.209) -2.58  (0.991)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, treatment-by-visit, baseline CASA-Q Cough impact score, baseline CASA-Q Cough impact score-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2475
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 1.81
Confidence Interval 95%
-1.26 to 4.88
Parameter Dispersion
Type: Standard Error of the mean
Value: 1.564
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo

20.Secondary Outcome
Title Proportion of Patient's Global Impression of Change (PGI-C) Responders at 52 Weeks: Patient Reported Outcomes (PROs)
Hide Description Patient's Global Impression of Change (PGI-C) responders are defined as 'Very much better'/ 'Much better'/ 'A little better'/ 'No change'.
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Number (95% Confidence Interval)
Unit of Measure: percentage of participants
53.88
(47.27 to 60.36)
61.70
(56.34 to 66.79)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Logistic regression with term treatment
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0690
Comments [Not Specified]
Method Regression, Logistic
Comments [Not Specified]
Method of Estimation Estimation Parameter Odds Ratio (OR)
Estimated Value 1.379
Confidence Interval 95%
0.98 to 1.95
Estimation Comments Nintedanib 150 mg bid versus Placebo
21.Secondary Outcome
Title Change From Baseline in EuroQol 5-Dimensional Quality of Life Questionnaire (EQ-5D) Health State up to 52 Weeks : Patient Reported Outcomes (PROs)
Hide Description The EuroQol 5-dimensional Health State is based on a visual analog scale (EQ-VAS) representing the general patient's health state labelled from 100 (best imaginable health state) to 0 (worst imaginable health state). A higher score indicating a better health state. Change from baseline is calculated as the difference between health state at week 12, 24 and 52 respectively and health state at baseline as measured by the scale.
Time Frame baseline, 12 weeks, 24 weeks and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Mean (Standard Deviation)
Unit of Measure: points on a scale
12 weeks (N=207, 306) -1.48  (15.60) -0.57  (16.97)
24 weeks (N=204, 297) -4.86  (16.94) -1.10  (16.81)
52 weeks (N=178, 265) -5.60  (17.67) -2.52  (16.95)
22.Secondary Outcome
Title Risk of an Acute IPF Exacerbation Over 52 Weeks
Hide Description The incidence rate of exacerbations (calculated as the number of patients with at least 1 acute IPF exacerbation divided by the total number of years at risk in years*100)
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: Participants/Year *100
10.2 3.9
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments The log of the risk ratio was assumed to follow a normal distribution with mean 0 and variance equal to the sum of the reciprocals of the number of patients with at least one exacerbation in each treatment arm.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.0070
Comments [Not Specified]
Method Normal distribution
Comments Risk ratio was calculated as the ratio of risk of exacerbation in both treatment groups.
Method of Estimation Estimation Parameter Risk Ratio (RR)
Estimated Value 0.38
Confidence Interval 95%
0.19 to 0.77
Estimation Comments Nintedanib 150 mg bid versus Placebo
23.Secondary Outcome
Title Time to Death Over 52 Weeks
Hide Description

Due to rare events, the median of time to event is not calculable, thus the percentages of patients who did or did not experienced death before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.

Failure is the proportion of patients who died over 52 weeks (373 days time-period).

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 9.1 6.7
Censored 90.9 93.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard ratio is based on a Cox´s regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2995
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.74
Confidence Interval 95%
0.40 to 1.35
Estimation Comments Nintedanib 150 mg bid versus Placebo
24.Secondary Outcome
Title Time to Death Due to Respiratory Cause Over 52 Weeks (Adjudicated)
Hide Description

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death due to respiratory causes before or at 372 days after randomisation or last contact date (whichever occurs first) are reported.

Failure is the the proportion of patients who died due to respiratory causes over 52 weeks (373 days time-period).

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 5.0 4.3
Censored 95.0 95.7
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.6654
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.86
Confidence Interval 95%
0.39 to 1.90
Estimation Comments Nintedanib 150 mg bid versus Placebo
25.Secondary Outcome
Title Time to On-treatment Death
Hide Description

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not die before or at last trial medication intake + 28 days were censored at last trial medication intake + 28 days and reported.

Failure is the the proportion of patients who died on-treatment.

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 7.8 4.9
Censored 92.2 95.1
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard ratio is based on a Cox´s regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2209
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.68
Confidence Interval 95%
0.34 to 1.35
Estimation Comments Nintedanib 150 mg bid versus Placebo
26.Secondary Outcome
Title Time to Death or Lung Transplant Over 52 Weeks
Hide Description Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experience event (death or lung transplant) before or at 372 days after randomisation or last contact date (whichever occurs first) are reported. Failure is the proportion of patients who died or had lung transplant over 52 weeks (373 days time-period).
Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 10.0 6.7
Censored 90.0 93.3
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.1664
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.67
Confidence Interval 95%
0.37 to 1.21
Estimation Comments Nintedanib 150 mg bid versus Placebo
27.Secondary Outcome
Title Time to Death or Lung Transplant or Qualifying for Lung Transplant Over 52 Weeks.
Hide Description

Due to rare events, the median of time to event is not calculable, thus the percentages of participants who did or did not experienced death or lung transplant or qualifying for lung transplant over 52 weeks are reported. A patient was considered qualifying for lung transplant by the investigator if he or she fulfilled the following criteria:

FVC <45% predicted or Carbon monoxide diffusion capacity (DL(CO)) <30% pred or Oxygen saturation on pulse oximetry (SpO2) <88% at rest, at sea level (to be adapted for other heights).

These criteria were evaluated by investigators judgement. Failure is the proportion of patients who died or had lung transplant or qualified for lung transplant over 52 weeks (373 days time-period).

Time Frame 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 219 329
Measure Type: Number
Unit of Measure: percentage of participants
Failure 23.7 19.5
Censored 76.3 80.5
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Hazard ratio is based on Cox´s regression model with terms for treatment, gender, age and height.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2123
Comments [Not Specified]
Method Log Rank
Comments [Not Specified]
Method of Estimation Estimation Parameter Hazard Ratio (HR)
Estimated Value 0.80
Confidence Interval 95%
0.55 to 1.16
Estimation Comments Nintedanib 150 mg bid versus Placebo
28.Secondary Outcome
Title Change From Baseline in SpO2 (Oxygen Saturation, Expressed in Percent) at Rest up Over 52 Weeks
Hide Description Means presented are the adjusted means. Adjusted mean is based on all analyzed patients in the model (not only patients with a change from baseline to week 52)
Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 212 320
Mean (Standard Error)
Unit of Measure: percent of oxygen saturation
-0.66  (0.174) -0.39  (0.149)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures (MMRM), with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline SpO2, baseline SpO2-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2032
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.27
Confidence Interval 95%
-0.15 to 0.69
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.213
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

29.Secondary Outcome
Title Change From Baseline in Carbon Monoxide Diffusion Capacity (DLCO) at Rest Over 52 Weeks
Hide Description Means provided are the adjusted means and are based on all analysed patients in the model (not only patients with a change from baseline to week 52).
Time Frame baseline and 52 weeks
Hide Outcome Measure Data
Hide Analysis Population Description
Treated Set (Only patients with observed cases (OC) values were analysed)
Arm/Group Title Placebo Nintedanib 150 mg Bid
Hide Arm/Group Description:
Oral administration of Placebo matching nintedanib soft gelatine capsules

Oral administration of soft gelatine capsules of nintedanib 150mg twice daily (bid).

Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.

Overall Number of Participants Analyzed 202 302
Mean (Standard Error)
Unit of Measure: mmol/min/kPa
-0.400  (0.0843) -0.286  (0.0729)
Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Placebo, Nintedanib 150 mg Bid
Comments Mixed Model for Repeated Measures with fixed effects for treatment, visit, gender, age, height, treatment-by-visit, baseline DLCO (HGB Corrected) [mmol/min/kPa], baseline DLCO (HGB Corrected) [mmol/min/kPa]-by-visit and random effect for patient.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.2600
Comments [Not Specified]
Method Mixed Models Analysis
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value 0.113
Confidence Interval 95%
-0.084 to 0.310
Parameter Dispersion
Type: Standard Error of the mean
Value: 0.1005
Estimation Comments

Within-patient errors are modelled by compound symmetry covariance matrix.

Nintedanib 150 mg bid versus Placebo.

Time Frame From the first drug administration until 28 days after the last drug administration, up to 425 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Placebo Nintedanib 150mg Bid
Hide Arm/Group Description Oral administration of Placebo matching nintedanib soft gelatine capsules. Oral administration of soft gelatine capsules of Nintedanib 150 mg twice daily (bid). Dose interruption and reduction to 100 mg bid dose were allowed to manage adverse events.
All-Cause Mortality
Placebo Nintedanib 150mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Hide Serious Adverse Events
Placebo Nintedanib 150mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   72/219 (32.88%)   98/329 (29.79%) 
Blood and lymphatic system disorders     
Anaemia  1  2/219 (0.91%)  0/329 (0.00%) 
Thrombocytopenia  1  1/219 (0.46%)  0/329 (0.00%) 
Cardiac disorders     
Acute myocardial infarction  1  0/219 (0.00%)  2/329 (0.61%) 
Angina pectoris  1  2/219 (0.91%)  1/329 (0.30%) 
Aortic valve stenosis  1  0/219 (0.00%)  2/329 (0.61%) 
Atrial fibrillation  1  1/219 (0.46%)  1/329 (0.30%) 
Atrioventricular block  1  1/219 (0.46%)  0/329 (0.00%) 
Atrioventricular block second degree  1  0/219 (0.00%)  1/329 (0.30%) 
Bradycardia  1  1/219 (0.46%)  1/329 (0.30%) 
Cardiac arrest  1  2/219 (0.91%)  0/329 (0.00%) 
Cardiac disorder  1  0/219 (0.00%)  1/329 (0.30%) 
Cardiac failure  1  1/219 (0.46%)  2/329 (0.61%) 
Cardiac failure acute  1  1/219 (0.46%)  0/329 (0.00%) 
Cardio-respiratory arrest  1  1/219 (0.46%)  0/329 (0.00%) 
Cardiomegaly  1  0/219 (0.00%)  1/329 (0.30%) 
Cor pulmonale  1  1/219 (0.46%)  1/329 (0.30%) 
Coronary artery disease  1  0/219 (0.00%)  1/329 (0.30%) 
Myocardial infarction  1  1/219 (0.46%)  3/329 (0.91%) 
Pericardial effusion  1  0/219 (0.00%)  1/329 (0.30%) 
Right ventricular failure  1  0/219 (0.00%)  1/329 (0.30%) 
Tachycardia  1  1/219 (0.46%)  0/329 (0.00%) 
Ventricular dysfunction  1  0/219 (0.00%)  1/329 (0.30%) 
Ear and labyrinth disorders     
Vertigo positional  1  0/219 (0.00%)  1/329 (0.30%) 
Eye disorders     
Cataract  1  0/219 (0.00%)  1/329 (0.30%) 
Orbital apex syndrome  1  1/219 (0.46%)  0/329 (0.00%) 
Retinal artery occlusion  1  1/219 (0.46%)  0/329 (0.00%) 
Retinal detachment  1  0/219 (0.00%)  1/329 (0.30%) 
Gastrointestinal disorders     
Colitis ulcerative  1  0/219 (0.00%)  1/329 (0.30%) 
Constipation  1  0/219 (0.00%)  2/329 (0.61%) 
Diarrhoea  1  1/219 (0.46%)  1/329 (0.30%) 
Diverticulum  1  1/219 (0.46%)  0/329 (0.00%) 
Duodenal ulcer perforation  1  0/219 (0.00%)  1/329 (0.30%) 
Gastric ulcer  1  0/219 (0.00%)  1/329 (0.30%) 
Haematochezia  1  0/219 (0.00%)  1/329 (0.30%) 
Haemorrhoids  1  0/219 (0.00%)  2/329 (0.61%) 
Inguinal hernia  1  0/219 (0.00%)  1/329 (0.30%) 
Intestinal haemorrhage  1  1/219 (0.46%)  0/329 (0.00%) 
Melaena  1  1/219 (0.46%)  0/329 (0.00%) 
Pancreatitis acute  1  0/219 (0.00%)  1/329 (0.30%) 
Rectal haemorrhage  1  0/219 (0.00%)  1/329 (0.30%) 
General disorders     
Asthenia  1  2/219 (0.91%)  0/329 (0.00%) 
Chest pain  1  2/219 (0.91%)  1/329 (0.30%) 
Disease progression  1  0/219 (0.00%)  1/329 (0.30%) 
Gait disturbance  1  1/219 (0.46%)  0/329 (0.00%) 
Sudden death  1  0/219 (0.00%)  1/329 (0.30%) 
Hepatobiliary disorders     
Cholelithiasis  1  0/219 (0.00%)  1/329 (0.30%) 
Liver injury  1  0/219 (0.00%)  1/329 (0.30%) 
Non-alcoholic steatohepatitis  1  0/219 (0.00%)  1/329 (0.30%) 
Infections and infestations     
Appendicitis  1  0/219 (0.00%)  1/329 (0.30%) 
Atypical pneumonia  1  0/219 (0.00%)  2/329 (0.61%) 
Bacteraemia  1  1/219 (0.46%)  0/329 (0.00%) 
Bronchitis  1  0/219 (0.00%)  6/329 (1.82%) 
Bronchopneumonia  1  1/219 (0.46%)  1/329 (0.30%) 
Cellulitis  1  1/219 (0.46%)  0/329 (0.00%) 
Chronic sinusitis  1  1/219 (0.46%)  0/329 (0.00%) 
Diverticulitis  1  0/219 (0.00%)  1/329 (0.30%) 
Herpes simplex meningoencephalitis  1  0/219 (0.00%)  1/329 (0.30%) 
Herpes zoster  1  2/219 (0.91%)  0/329 (0.00%) 
Infection  1  1/219 (0.46%)  1/329 (0.30%) 
Infective aneurysm  1  1/219 (0.46%)  0/329 (0.00%) 
Influenza  1  0/219 (0.00%)  1/329 (0.30%) 
Lower respiratory tract infection  1  2/219 (0.91%)  0/329 (0.00%) 
Lung infection  1  0/219 (0.00%)  1/329 (0.30%) 
Mycobacterial infection  1  1/219 (0.46%)  0/329 (0.00%) 
Pathogen resistance  1  1/219 (0.46%)  0/329 (0.00%) 
Peritonitis  1  0/219 (0.00%)  1/329 (0.30%) 
Pneumonia  1  11/219 (5.02%)  18/329 (5.47%) 
Pulmonary tuberculosis  1  0/219 (0.00%)  1/329 (0.30%) 
Respiratory tract infection  1  3/219 (1.37%)  1/329 (0.30%) 
Sepsis  1  1/219 (0.46%)  0/329 (0.00%) 
Staphylococcal infection  1  1/219 (0.46%)  0/329 (0.00%) 
Tuberculosis  1  1/219 (0.46%)  1/329 (0.30%) 
Urinary tract infection  1  1/219 (0.46%)  1/329 (0.30%) 
Urosepsis  1  0/219 (0.00%)  1/329 (0.30%) 
Viral upper respiratory tract infection  1  0/219 (0.00%)  1/329 (0.30%) 
Injury, poisoning and procedural complications     
Burns third degree  1  0/219 (0.00%)  1/329 (0.30%) 
Contusion  1  0/219 (0.00%)  1/329 (0.30%) 
Fall  1  1/219 (0.46%)  0/329 (0.00%) 
Femur fracture  1  1/219 (0.46%)  0/329 (0.00%) 
Joint dislocation  1  1/219 (0.46%)  0/329 (0.00%) 
Laceration  1  0/219 (0.00%)  1/329 (0.30%) 
Ligament rupture  1  0/219 (0.00%)  1/329 (0.30%) 
Ligament sprain  1  1/219 (0.46%)  0/329 (0.00%) 
Lower limb fracture  1  1/219 (0.46%)  0/329 (0.00%) 
Rib fracture  1  1/219 (0.46%)  2/329 (0.61%) 
Road traffic accident  1  1/219 (0.46%)  0/329 (0.00%) 
Spinal compression fracture  1  1/219 (0.46%)  0/329 (0.00%) 
Tendon rupture  1  1/219 (0.46%)  0/329 (0.00%) 
Investigations     
Arteriogram coronary  1  0/219 (0.00%)  1/329 (0.30%) 
Chest X-ray abnormal  1  0/219 (0.00%)  1/329 (0.30%) 
Transaminases increased  1  1/219 (0.46%)  2/329 (0.61%) 
Metabolism and nutrition disorders     
Decreased appetite  1  1/219 (0.46%)  0/329 (0.00%) 
Diabetes mellitus  1  1/219 (0.46%)  0/329 (0.00%) 
Diabetes mellitus inadequate control  1  2/219 (0.91%)  0/329 (0.00%) 
Hyponatraemia  1  0/219 (0.00%)  1/329 (0.30%) 
Metabolic acidosis  1  1/219 (0.46%)  0/329 (0.00%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  1/219 (0.46%)  0/329 (0.00%) 
Intervertebral disc protrusion  1  0/219 (0.00%)  2/329 (0.61%) 
Lumbar spinal stenosis  1  1/219 (0.46%)  1/329 (0.30%) 
Rotator cuff syndrome  1  0/219 (0.00%)  1/329 (0.30%) 
Synovitis  1  0/219 (0.00%)  1/329 (0.30%) 
Neoplasms benign, malignant and unspecified (incl cysts and polyps)     
Adenocarcinoma gastric  1  1/219 (0.46%)  0/329 (0.00%) 
Basal cell carcinoma  1  1/219 (0.46%)  1/329 (0.30%) 
Bladder cancer  1  0/219 (0.00%)  1/329 (0.30%) 
Chloroma  1  0/219 (0.00%)  1/329 (0.30%) 
Colon cancer  1  0/219 (0.00%)  1/329 (0.30%) 
Laryngeal squamous cell carcinoma  1  1/219 (0.46%)  0/329 (0.00%) 
Lung adenocarcinoma  1  0/219 (0.00%)  1/329 (0.30%) 
Lung adenocarcinoma metastatic  1  1/219 (0.46%)  0/329 (0.00%) 
Lung neoplasm malignant  1  2/219 (0.91%)  0/329 (0.00%) 
Neurofibroma  1  0/219 (0.00%)  1/329 (0.30%) 
Non-small cell lung cancer  1  0/219 (0.00%)  1/329 (0.30%) 
Renal cancer  1  0/219 (0.00%)  1/329 (0.30%) 
Squamous cell carcinoma  1  1/219 (0.46%)  0/329 (0.00%) 
Nervous system disorders     
Aphasia  1  0/219 (0.00%)  1/329 (0.30%) 
Cerebral infarction  1  0/219 (0.00%)  2/329 (0.61%) 
Cerebrovascular disorder  1  1/219 (0.46%)  0/329 (0.00%) 
Encephalopathy  1  0/219 (0.00%)  1/329 (0.30%) 
Hypoaesthesia  1  0/219 (0.00%)  1/329 (0.30%) 
Loss of consciousness  1  1/219 (0.46%)  1/329 (0.30%) 
Monoparesis  1  0/219 (0.00%)  1/329 (0.30%) 
Piriformis syndrome  1  0/219 (0.00%)  1/329 (0.30%) 
Syncope  1  2/219 (0.91%)  0/329 (0.00%) 
Transient ischaemic attack  1  0/219 (0.00%)  1/329 (0.30%) 
Psychiatric disorders     
Depression  1  0/219 (0.00%)  1/329 (0.30%) 
Suicide attempt  1  0/219 (0.00%)  1/329 (0.30%) 
Renal and urinary disorders     
Renal colic  1  0/219 (0.00%)  1/329 (0.30%) 
Respiratory, thoracic and mediastinal disorders     
Acute respiratory distress syndrome  1  1/219 (0.46%)  0/329 (0.00%) 
Acute respiratory failure  1  0/219 (0.00%)  1/329 (0.30%) 
Dyspnoea  1  3/219 (1.37%)  2/329 (0.61%) 
Haemoptysis  1  2/219 (0.91%)  0/329 (0.00%) 
Hypoxia  1  3/219 (1.37%)  4/329 (1.22%) 
Idiopathic pulmonary fibrosis  1  28/219 (12.79%)  22/329 (6.69%) 
Pleural effusion  1  0/219 (0.00%)  1/329 (0.30%) 
Pneumomediastinum  1  0/219 (0.00%)  1/329 (0.30%) 
Pneumothorax  1  1/219 (0.46%)  2/329 (0.61%) 
Pulmonary arterial hypertension  1  2/219 (0.91%)  0/329 (0.00%) 
Pulmonary embolism  1  0/219 (0.00%)  4/329 (1.22%) 
Pulmonary hypertension  1  3/219 (1.37%)  6/329 (1.82%) 
Respiratory acidosis  1  1/219 (0.46%)  0/329 (0.00%) 
Respiratory failure  1  5/219 (2.28%)  2/329 (0.61%) 
Sleep apnoea syndrome  1  0/219 (0.00%)  1/329 (0.30%) 
Upper respiratory tract inflammation  1  1/219 (0.46%)  0/329 (0.00%) 
Skin and subcutaneous tissue disorders     
Subcutaneous emphysema  1  0/219 (0.00%)  1/329 (0.30%) 
Surgical and medical procedures     
Coronary angioplasty  1  0/219 (0.00%)  1/329 (0.30%) 
Lung transplant  1  0/219 (0.00%)  1/329 (0.30%) 
Tracheostomy  1  1/219 (0.46%)  0/329 (0.00%) 
Vascular disorders     
Aortic aneurysm  1  1/219 (0.46%)  0/329 (0.00%) 
Aortic aneurysm rupture  1  0/219 (0.00%)  1/329 (0.30%) 
Aortic intramural haematoma  1  0/219 (0.00%)  1/329 (0.30%) 
Deep vein thrombosis  1  2/219 (0.91%)  0/329 (0.00%) 
Hypertension  1  0/219 (0.00%)  2/329 (0.61%) 
Hypertensive crisis  1  1/219 (0.46%)  1/329 (0.30%) 
Hypotension  1  1/219 (0.46%)  1/329 (0.30%) 
Phlebitis  1  1/219 (0.46%)  0/329 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 16.1
Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
Placebo Nintedanib 150mg Bid
Affected / at Risk (%) Affected / at Risk (%)
Total   193/219 (88.13%)   308/329 (93.62%) 
Gastrointestinal disorders     
Abdominal pain  1  7/219 (3.20%)  30/329 (9.12%) 
Abdominal pain upper  1  6/219 (2.74%)  18/329 (5.47%) 
Constipation  1  10/219 (4.57%)  19/329 (5.78%) 
Diarrhoea  1  39/219 (17.81%)  207/329 (62.92%) 
Nausea  1  16/219 (7.31%)  86/329 (26.14%) 
Vomiting  1  7/219 (3.20%)  34/329 (10.33%) 
General disorders     
Fatigue  1  20/219 (9.13%)  26/329 (7.90%) 
Infections and infestations     
Bronchitis  1  17/219 (7.76%)  26/329 (7.90%) 
Nasopharyngitis  1  34/219 (15.53%)  48/329 (14.59%) 
Respiratory tract infection  1  13/219 (5.94%)  18/329 (5.47%) 
Upper respiratory tract infection  1  24/219 (10.96%)  30/329 (9.12%) 
Investigations     
Weight decreased  1  2/219 (0.91%)  37/329 (11.25%) 
Metabolism and nutrition disorders     
Decreased appetite  1  10/219 (4.57%)  42/329 (12.77%) 
Musculoskeletal and connective tissue disorders     
Arthralgia  1  11/219 (5.02%)  8/329 (2.43%) 
Back pain  1  13/219 (5.94%)  20/329 (6.08%) 
Nervous system disorders     
Headache  1  7/219 (3.20%)  22/329 (6.69%) 
Respiratory, thoracic and mediastinal disorders     
Cough  1  31/219 (14.16%)  38/329 (11.55%) 
Dyspnoea  1  22/219 (10.05%)  25/329 (7.60%) 
Idiopathic pulmonary fibrosis  1  15/219 (6.85%)  13/329 (3.95%) 
Vascular disorders     
Hypertension  1  11/219 (5.02%)  11/329 (3.34%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, 16.1
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI's intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT01335477    
Other Study ID Numbers: 1199.34
2010-024252-29 ( EudraCT Number: EudraCT )
First Submitted: April 13, 2011
First Posted: April 14, 2011
Results First Submitted: November 14, 2014
Results First Posted: February 13, 2015
Last Update Posted: July 25, 2016